JP4269030B2 - Random access slide dyeing device that controls heating of individual slides - Google Patents

Abstract

There is described a microscope slide stainer, comprising: three waste bottles and a large external trap bottle for aqueous waste; four solenoid valves, each associated with a respective one of the three waste bottles and the external trap bottle, for controlling to which bottle aspirated liquid will be directed; and a fifth solenoid valve for allowing a direct connection between a vacuum pump and an overflow trap, wherein the four bottles are connected to the overflow trap, and the solenoid valves are operated under computer control; an aspirator head, wherein if the fifth solenoid valve and one of the four valves are appropriately opened, as specified in the staining protocol, the pump turned on, and the aspirator head positioned so as to aspirate liquid, the liquid is directed to follow the only path available and be collected in the bottle associated with the open valve.

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a slide staining apparatus for supplying and removing a reagent from a biological tissue fragment attached to a microscope slide.
[0002]
[Background Art and Problems to be Solved by the Invention]
Tissue fragments or cell monolayers are usually examined by microscopy for both research and clinical diagnostic purposes. Thin tissue fragments or cell samples are generally 1-10 microns thick and are nearly transparent in the untreated state. In order to look at various histological forms, a wide range of staining techniques have been developed over the years to highlight various cells or extracellular components of the tissue. Histochemical staining, or “special staining” in general terms, stains various chemical components by using chemical reactions. In immunohistochemical staining, an antibody is used as a probe, and a specific protein is generally stained with an enzyme precipitate of the stained precipitate. Each of these histochemical and immunohistochemical stains requires the addition and removal of reagents in a defined sequence at a defined temperature for a specific time. Therefore, a need arises for a slide dyeing apparatus that can perform various kinds of dyeing at the same time under computer control, as defined by an engineer.
[0003]
An early slide staining apparatus for immunohistochemistry is described by David Brigati MD in US Pat. No. 4,731,335. According to the disclosure of this patent, the microscope slides are placed close to each other to form a pore gap. The pair of slides is mounted in a holder, which can be moved in three dimensions by a mechanical arm. If it is necessary to heat the slides, move all the slides together into a humidification / heating chamber. Therefore, with this design, a random access scheme is not possible.
[0004]
In another slide dyeing apparatus in US Pat. No. 4,043,292 by Rogers and Sullivan, slides are mounted on a rotating carousel. Their invention heats the slide by passing hot air over the slide. Thus, all slides are heated to the same temperature.
[0005]
Wooton, McLeod and Read disclose another slide dyeing apparatus that can be heated in US Pat. No. 5,231,029. In the present invention, a steam chamber is provided to heat the slide. The humidity in the steam chamber is designed to be close to 100%. If the slide needs to be heated, it is placed in the chamber. Since the slides are either outside or inside the chamber, all the slides need to be heated to the same heating temperature, ie, approximately steam temperature (100 ° C.).
[0006]
A recently published batch slide staining apparatus marketed by Ventana Medical System, Inc. is disclosed in US Pat. No. 5,595,707 by Copeland et al. According to the disclosure of this patent, the slide is placed on a rotating carousel, on which the reagent is added to the surface of the slide and washed away. The slide dyeing apparatus of the present invention includes a heating chamber heated by hot air. A temperature sensor is in the chamber and provides temperature feedback to the microprocessor. As with the other slide staining devices described above, all slides need to be heated to the same temperature.
[0007]
[Means for Solving the Problems]
The present invention relates to an improved slide staining apparatus for supplying and removing reagents from biological tissue fragments attached to a microscope slide. The improvement relates to the random access function of the slide staining apparatus. That is, to perform any of a series of procedures on any of a plurality of biological samples attached to a microscope slide. Since various procedures require heating at different times to increase the chemical reaction rate, means have been developed to heat the slides to different temperatures independently of other slide temperatures. The present invention allows each slide to be heated to a unique specified temperature.
[0008]
Modifications can be made to any of the above systems, and the heater control system can be duplicated to provide multiple levels of heating control functions. For example, a commercially available commercial temperature cycler using four types of heating blocks sharing the same microprocessor can be used. However, the type of temperature control mechanism of the fixed wiring that heats and cools the four types of blocks becomes expensive and complicated as the number of individual samples increases. For example, in the preferred embodiment of the present invention, 49 separate heating locations are described. Assuming that two wires supply power to the heater and two wires provide temperature feedback from each temperature sensor, a total of 196 wires need to be connected between the separate heater and the computer control circuit. There is. Applying all of these wires to the service loop between the computer in place and the moving slide dyeing apparatus creates additional difficulties and increases manufacturing and service costs.
[0009]
According to one configuration of the invention, the moving plate, preferably a carousel, supports a plurality of microscope slides carrying biological samples. In particular, a plurality of flat heating stations are provided on the platform, each heating station supporting at least one microscope slide. The heating station is individually controlled to control the heating temperature of the slide.
[0010]
According to another configuration of the invention, the plurality of heaters, each of which can heat at least one slide, is connected to a mobile platform that supports the plurality of microscope slides. Each heater includes a heating element set, each set having at least one heating element. Temperature control electronics mounted on the mobile platform can power the heating elements to heat each heating element set to a separate temperature. A user interface mounted remotely from the mobile platform directs the microscope slide to the desired temperature via a communication link with temperature control electronics.
[0011]
The communication link is a wiring group, and the number of wirings is preferably smaller than the number of heating elements. To this end, the temperature control electronics can include a shift register that receives control data from the user interface, and the plurality of shift registers of the plurality of temperature control circuits are daisy chained. It is also possible to provide individual temperature sensors to supply temperature feedback information to the temperature control electronics.
[0012]
DETAILED DESCRIPTION OF THE INVENTION
The above and other objects, configurations and advantages of the present invention will become apparent from the more detailed description of the preferred embodiments of the present invention with reference to the accompanying drawings. In the accompanying drawings, like reference numerals designate like parts throughout the different views. The drawings are not necessarily to scale, emphasis being placed on illustrating the principles of the invention.
[0013]
FIG. 1 is a perspective view showing a first embodiment of the present invention. In general, a slide staining apparatus 1 according to the first embodiment includes a substantially circular assembly base 2, a slide rotor 3 rotatable on the assembly base 2, a reagent rotor 4 rotatable on the assembly base, and liquid distribution and A removal station 5 is provided.
[0014]
The slide rotor 3 is rotated by being driven by a servo motor (not shown), and holds ten slide frames 6 that can be inserted and removed in the radial direction. A plan view of a single slide frame 6 is shown in FIG. In this case, the positions of five slides each having a tissue sample are shown in 7a-7e. The slide frame 6 includes a slide frame base 8 shown in FIG. The slide frame base 8 includes a heating area 9, which is below the sliding position 7a-7e and incorporates a resistance heating element (not shown). The heating element is integrally formed in the slide frame base 8. Electric power necessary for the heating element is supplied from the assembly base 2 to the slide frame 6 via the first and second contacts 10. Further, the third and fourth contacts 11 can sense the temperature of the heating region through a thermocouple formed integrally with the slide frame base 8. In practice, a total of three connectors are required. This is because contacts 10 and 11 share the same ground connection. Therefore, one of the connectors 11 remains unused.
[0015]
The slide frame housing 12 is overlaid on the slide frame base. FIG. 4 is a plan view of the slide frame housing 12 showing a substantially rigid plastic or metal frame 13 having five elliptical holes 14a-14e corresponding to each of the slide positions 7a-7e. A silicon rubber gasket 15 is also provided under the frame 13. According to FIG. 2, a slide frame housing 12 comprising a gasket 15 and a frame 13 is fixed to the slide frame base 8 by two Allen bolts 16 and is placed at each of the slide positions 7a-7e. Form individually sealed voids about 0.2-0.4 inches deep on the tissue sample slide. As a result, a total of 3 ml of reagent and / or rinse solution can be placed in contact with each tissue sample on the slide. However, the maximum amount is desirably 2 ml. Since the frame 13 presses the silicon gasket 15 against a microscope slide (not shown), the gap above each frame position is sealed to each other.
[0016]
FIG. 5 is a plan view of the slide frame base 8 having five microscope slides 17 at the positions indicated by 7a-7e in FIG. The area of each slide 17 that forms a gap is delimited by a silicon rubber gasket 15 and holes 14a-14e and is indicated by a generally rectangular line 18 that indicates the chamber wall. A region indicated by hatching indicates a region of the slide frame base 8 including the heating element 9. The entire heating area (shaded area) is heated to the same temperature, and the group of five slides is heated to the same desired temperature. The portion of each slide 17 that is not on the heating area is generally not loaded with a biological tissue specimen. This part is used for label display.
[0017]
FIG. 6 is a cross-sectional view of the assembled slide frame base 8 and housing 12, which are collectively referred to as the slide frame 6. The microscope slide 17 is held at a position between the slide frame base 8 and the housing 12. The slide frame 6 is placed on the slide rotor 3. This figure shows the electrical connection between the slide frame 6 and the edge connector 19. There are four edge connectors (contacts 10 and 11 in FIGS. 2 and 3) per slide frame 6. The electrical wiring reaches the terminal below the side rotor 3 from the edge connector 19 via the slide rotor and the insulated supply path 20. At this time, the wiring is connected to a terminal of a power supply or a control circuit (not shown).
[0018]
FIG. 7 is a schematic diagram showing two of the ten sets of heaters 91 and sensors 92 that can be placed on the slide rotor of the apparatus. The heater is illustrated as a resistance element and corresponds to the heating region (shaded portion) in FIG. Contacts 10 and 11 share a common ground connection and leave one of the four connectors unused. Each circuit is connected to the temperature controller 21. Three wires extend from the slide frame to the temperature controller 21. That is, the heater power wiring 22, the sensor conductor 23 and the ground connection 24. The temperature controller 21 is installed at a fixed position on the assembly base 2. Since the heater and the sensor frequently move, the heater and the sensor are connected to the temperature controller 21 at a fixed position through a service loop (not shown). The service loop includes wiring from each of the edge connectors 19. The wiring is long enough so that the service loop can move around the slide rotor axis as the slide rotor rotates. The slide rotor 3 does not rotate more than one turn in any direction. It is desirable that the wires in the service loop be bound with a wire so that the individual wires are not entangled or drawn under the slide rotor 3. Since there are three wires per circuit (wirings 22-24) and the slide rotor 3 has ten slide frames 6, the service loop includes at least 30 wires.
[0019]
According to FIG. 1, there is a reagent rotor 4 on the slide rotor 3. The reagent rotor rotates in the same manner on the assembly base 2 and is driven by computer control (not shown) by another servomotor (not shown). The reagent rotor 4 and the slide rotor 3 rotate independently of each other. The reagent rotor 4 can hold up to ten cartridge frames 25. Each of these cartridge frames 25 can be removed from the reagent rotor 4 and can be selectively attached to any one of the 10 connectable positions. Each cartridge frame 25 can hold five cartridge pumps 46.
[0020]
In general, the dispensing station 5 includes a soft hammer 26 that engages a portion of the cartridge pump 46. The structure of the cartridge pump 46 is such that liquid is dispensed when a portion of the cartridge pump 46 (referred to as the metering chamber 42) is compressed. The reagent rotor can be rotated to align the desired cartridge pump 46 with the hammer 26 and can be dispensed from any of the plurality of cartridge pumps. This allows a precisely metered amount of reagent to be dispensed to all slides under the cartridge pump 46 adjacent to the actuator 26. FIG. 8 shows the dispensing mechanism from the cartridge pump 46 in more detail. The hammer 26 is driven by a solenoid or linear step motor 43 mounted on a front wall 44 attached to the assembly base 2. In FIG. 8, the hammer is shown compressing a portion of the metering chamber 42 of the cartridge pump. It is important to be able to adjust the rate at which the hammer 26 compresses the metering chamber 42. In the absence of this, compression may be too rapid and reagent ejection from the metering chamber 42 may be too strong, damaging the underlying tissue fragment. Therefore, linear step motors are preferred over solenoids. Alternatively, the reciprocating hammer of the dispensing actuator can be in the form of a cam and driven by a rotary motor to engage the metering chamber 42 and rotate the cam to compress the metering chamber.
[0021]
The cartridge pump 46 includes a liquid tank 45 and a metering chamber 42. The liquid tank 45 shown in the slide staining apparatus 1 of the first embodiment is a syringe barrel. The metering chamber 42 is made of a compressible elastic housing and includes a one-way inlet valve (not shown) and a one-way outlet valve (not shown), both arranged below the liquid flow. When the hammer 26 compresses the measuring chamber 42, the liquid reagent therein is ejected. When the compressive force is removed, the negative pressure generated by the expansion of the elastic housing so as to return to the original non-compressed shape causes the liquid to flow from the liquid tank 45 inward. In this way, the repeated compressive force of the metering chamber 42 will repeatedly dispense a small amount of reagent. Other cartridge pumps are shown in US patent application Ser. No. 08 / 887,178, filed Jul. 2, 1997 and in US Patent Application No. 09 / 020,983, filed Feb. 10, 1998. Which are hereby incorporated by reference.
[0022]
The dispensing station 5 further comprises means for dispensing the liquid from the large bottle (FIG. 9). The large liquid bottle 27 can supply the liquid via the rinse tube 28 onto the arbitrary microscope slide 17 on the arbitrary slide frame 6. Each large liquid bottle 27 is connected to a unique rinse tube 28. The large liquid bottle 27 is pressurized by a pump (not shown). Outflow tubes (not shown) from each large liquid bottle 27 pass through a valve 47 that controls the liquid flow rate from the bottle. A predetermined amount of liquid can be distributed on the slide 17 by setting the inside of the bottle 27 to a specified pressure, opening the valve for a fixed time under computer control (not shown). The liquid in the bottle 27 is water, salt water, alcohol or the like, and is repeatedly used in various procedures.
[0023]
The large liquid bottle 27 as shown in FIG. 9 is screwed into a female screw cap 48 fixed to the lower side of the horizontal upper wall 49 of the station frame. Compressed air from a compressor (not shown) is supplied to each large liquid bottle 27 via a pressure controller 50. A tube 51 from the pressure controller sends compressed air to the inlet of the large liquid bottle 27. The pressure acting on the liquid pushes up the liquid through the dip tube 52 and the rinse hose 53 when the pinch valve 47 is opened. A predetermined amount of liquid can be distributed through the rinse tube 28 in accordance with the time to open the pinch valve 47.
[0024]
The liquid dispensing and removal assembly 5 further comprises a liquid removal vacuum station adjacent to the rinse tube 28 (not shown in FIG. 1). In order to remove the liquid from the surface of the slide 17, the reagent rotor places the slide in the liquid removal vacuum station shown in the side cross-sectional views of FIGS. 10A and 10B. An external vacuum source (not shown) is directed through the trap flask 29 and finally reaches the vacuum hose terminating in the suction head 31. Tube connections are not shown in FIGS. 10A and 10B. The vacuum hose 30 and the suction head 31 are supported by the hose transport mechanism 54, thereby extending the suction head 31 into the gap of the slide frame 6 so that the liquid covering the tissue sample on the slide 17 can be removed. When the suction head comes into contact with the liquid, the liquid is sucked upward in the tube and collected in the trap flask 29.
[0025]
The vacuum hose transport mechanism 54 includes a motor 32. By attaching the reciprocating link 33 to the crank arm 34, the motor 32 moves the link 33 in the vertical direction. The bottom of the reciprocating link 33 is connected to a lever 55 that is pivotally attached to the station frame. The other end of the lever is connected to a vacuum hose clamp 35, which is connected via a pivot arm 36 to a plate 37 fixedly attached to the station frame. The pure effect of these connections is that the slide arm 33 is lowered vertically as the motor 32 rotates. Accordingly, the lever 55 pivots clockwise about its fulcrum, causing the hose clamp 35 to rotate up and away from the slide and be positioned on the two pivot arms 36 as shown in FIG. 10B. As the link electrical terminal 39 contacts the contact plate 38 connected to the station frame, the motor automatically stops as soon as the link 33 reaches both ends of its movement.
[0026]
Details of the suction head 31 are shown in FIGS. 11A and 11B. FIG. 11A is a cross-section of the suction head and shows a state where the suction head is lowered in the gap formed by the slide frame 6. The suction head 31 has an internal hollow manifold 40 through which a vacuum force is transmitted to the entire lower surface of the suction head 31. Eight holes 41 are provided on the lower surface of the suction head 31, and the suction force is transmitted through these holes. Since the microscope slide 17 is flat, the liquid on the slide surface spreads in two dimensions. Therefore, in order to completely remove the liquid from all parts of the microscope slide 17, a plurality of suction positions are necessary. In the present invention, this is realized by a suction head having a flat lower surface provided with a plurality of holes. The flat surface of the suction head 31 is placed close to and parallel to the microscope slide 17. The suction head only contacts the liquid, not the microscope slide itself. This is because the head does not damage the glass slide 17 or the biological specimen (not shown) it supports. If this is not the case and there is only one suction position such as from a pipette, the liquid at a position away from the suction device is not removed. Conversely, the liquid will adhere to the remote surface of the glass slide 17 due to the surface tension of the glass. As a result, the liquid remains and remains on the surface of the slide 17. Arranging the bottom surface of the suction head close to and parallel to the slide is also effective in reducing the surface tension during liquid suction. By arranging the bottom surface of the suction head close to and parallel to the microscope slide 17, a kind of pore gap is formed. This gap weakens the surface tension and ensures complete removal of the liquid.
[0027]
A computer (not shown) controls the function of the device. That is, the operator programs the computer with information such as the position of the reagent on the reagent rotor and the position of the slide on the slide rotor. At this time, the operator writes a program to execute a specific histochemical protocol on the tissue sample. What can be included as variables in these protocols are the special reagents used for the tissue sample, the time that the tissue sample can react with the reagent, whether the tissue sample is heated, and used to wash the reagent The rinse is then removed with the reagent and then applied to another reagent, and so on. The device has complete random access, ie access to any slide in any reagent in any order.
[0028]
A second preferred embodiment of the present invention is shown in FIG. As with the above embodiment, two independent carousels that rotate on the assembly base 56 are also provided. A large liquid bottle 57 is attached to a bridge 58 above the reagent rotor, which bridge extends across the width of the entire machine. A separate group of trap bottles 59 for collecting waste liquid is mounted on the side of the bridge 58 in a finely divided shelf. Tube connections and valves for the large liquid bottle 57 and trap bottle 59 are hidden behind the upper panel 60 and are not visible. A cartridge pump 62 or a slide (not shown) can be inserted by surrounding the front and side surfaces of the slide staining apparatus with a plastic glass case 61 and sliding the case sideways by hand. The slide is inserted and removed from the slide access door 63 at the center. The slide (not shown) is hidden behind the circular plate 64 above the slide and reagent rotor (not shown). Functions similar to the dispensing assembly (5 in FIG. 1) in the above embodiment are performed in a somewhat similar liquid handling assembly (not shown) in the liquid handling zone 65.
[0029]
FIG. 13 shows the individual mechanisms within the liquid handling zone 65, including a dispensing hammer 66 from a cartridge pump (not shown), a suction head 67 that removes liquid from the slide surface, a large liquid distribution port 68 and on the slide surface. An air mixing head 69 for diffusing and mixing the liquid. The electromechanical mechanism for compressing the metering chamber of the cartridge pump (not shown in FIG. 13) with the hammer 66 and distributing from the cartridge pump is similar to the above embodiment (FIG. 8). Reagent dispensed from a cartridge pump (not shown) flows through the generally rectangular hole in the platen 64 onto the slide.
[0030]
The suction head 67 also functions in the same manner as in the above embodiment. In order to simplify the linkage mechanism for lowering and raising the head 67, the head moves in the vertical direction at a low speed. This is illustrated in detail in FIGS. 14A and 14B. FIG. 14A shows a cross-sectional side view of the suction head in a lowered position within the gap formed by the microscope slide 75 (bottom surface) and slide chamber clip 76 (side wall). Similar to the first embodiment, a gasket (not shown) seals the surface where the slide chamber clip 76 contacts the microscope slide 75. Under computer control, the linear step motor 73 moves the suction head up and down (schematically shown in FIG. 15). Similar to the first embodiment, the suction head 67 includes a hollow manifold 74 connected to a vacuum source. Eight holes communicate between the bottom of the suction head 67 and the outside, and liquid is sucked through the holes. When the suction head 67 is evacuated and the head 67 is lowered to a position close to the slide, the liquid reagent at the top of the slide is sucked and collected in the trap bottle 59 (shown in FIG. 15). When the suction head 67 is not in use, it moves up to the upper position (FIG. 14B) and the slide rotor 77 can rotate freely.
[0031]
FIGS. 14A and 14B also show the physical location of the heating element 78, which is shown as a resistive element inside the rectangular box shown as diagonal lines. Since each slide rests directly on the heating element 78, heat is transferred directly to the microscope slide. A thermistor is incorporated in each heating element (not shown in FIGS. 14A and 14B). Since each of the 49 microscope slides 75 has its own heating element 78, the temperature of each slide 75 can be controlled separately. Electric power for the heating element 78 is directly supplied from a temperature control board 79 attached to the lower side of the slide rotor 77. Seven temperature control boards 79 of the same type are attached below the slide rotor 77 and arranged on the outer periphery at equal intervals. Each temperature control board supplies power to seven heating elements 78. Means for doing this will be described later with reference to FIGS. 17, 18, 18A-D.
[0032]
An important configuration of this embodiment is an apparatus that separates waste liquid removed from the surface of the slide, which was not emphasized in the first embodiment. FIG. 15 is a schematic diagram illustrating a method for performing this separation. Three types of waste liquid bottles 59 are attached to the apparatus. The device also includes a connection 70 and corresponds to a large external trap bottle 71, typically 10-20 liters, for aqueous waste. The four solenoid valves 80A-80D control which bottle the liquid to be sucked is introduced. These valves are controlled by a computer illustrated in a box labeled “Controller” 86. The valve 81 is a three-way valve. This valve allows a direct connection between the vacuum pump 82 and the overflow trap 83, or a connection between the pump and the outside world. When the aeration head 69 is in use, a direct connection to the outside world is required when the suction system needs to be bypassed. When the valves 80A and 81 are properly opened, the pump 82 is activated, the suction head 67 descends and sucks the liquid, and sends the liquid through the tube in the upward direction indicated by the arrow “liquid flow”. Next, the liquid is collected in the external trap bottle 71 through a prepared path. Valves 80B-80D perform a similar function for each trap bottle 59. A small overflow trap bottle 83 is also inserted in the line with its own liquid level sensor 93. This device is equipped to detect the overflow of waste liquid from any of the trap bottles 59 or the external trap bottle 71. When it overflows, the liquid enters the overflow trap bottle and is detected by the liquid level sensor. When this signal is sent to the controller 86, the controller stops the system and alerts the device operator's computer screen.
[0033]
According to FIG. 13, the liquid handling zone also comprises an aeration head 69. FIG. 15 shows the flow of air to the aeration head 69. The pump generates a high-speed air flow and sends it to the aeration head 69. The intake of air into the pump is performed via a three-way solenoid valve 81 (FIG. 15). By switching the solenoid valve 81 (FIG. 15) to bypass the suction system and trap bottles 59 and 71, outside air is sent directly to the pump. This high velocity air stream is concentrated on the slide. The aeration head 69 is reciprocated in the length direction of the slide by being pushed and pulled by a belt and pulley attached to a motor (not shown). The basic function of this system is to mix the liquid and diffuse it along the surface of the microscope slide by moving the air curtain back and forth along the length of the slide.
[0034]
The liquid handling zone 65 (FIG. 12) includes a large liquid distribution port 68 (FIG. 13). The function of the rinse tube 28 of the first embodiment (shown in FIG. 1) is incorporated into the single large liquid distribution port 68 of this preferred embodiment. Therefore, the slide is placed under the large liquid distribution port 68 regardless of the large liquid bottle from which the liquid is actually removed. FIG. 16 is a schematic view of a liquid path and a control valve. Each large liquid bottle 57 is connected to a pressure source generated by a pump 85. The pressure is transmitted to the large liquid bottle 57 via the pressure manifold 94. The solenoid valves 72 a to 72 f are installed between the large liquid distribution pod 68 and each large liquid bottle 57. Liquid flows out of the large liquid distribution port 68 only when one or more of the valves 72a-72f are open. A pressure switch 84 is also associated with the pressure manifold 94. The pressure switch 84 can sense the air amount or pressure in the manifold 94. When the pressure falls below a specified level, the switch communicates to the controller 86 and activates the pump 85. When the pump increases the air pressure in the pressure manifold, the pressure switch resets and stops the pump. In this way, a relatively constant pressure head is maintained in the pressure manifold 94.
[0035]
A distribution sensor 95 is provided below the large liquid distribution port 68 and confirms that liquid has been distributed when one of the solenoid valves 72a-72f is transiently opened. The distribution sensor 95 includes an optical sensor and an LED light source, and when the liquid is distributed from the large liquid distribution port 68, the liquid blocks the light beam. The change in resistance across the sensor resulting from the decrease in light intensity is communicated to the controller 86.
[0036]
The second preferred embodiment of the present invention has a function for individually heating 49 slides to different temperatures. The novel configuration of this embodiment is a method for individually controlling the amount of power received by each of the 49 heaters. Each heater also incorporates a temperature sensor. Each of these sensors must be connected to computer 86 for proper temperature feedback and control. In the first embodiment, a group of up to five slides is controlled by a single common temperature control mechanism. Each heating group had wiring directly connected to the temperature controller (FIG. 7). Since there are 10 groups of 3 wires per group (for heating, sensor feedback and shared ground) and slides, at least 30 wires were included in the service loop. If a similar system is used for 49 different heaters, as in this preferred embodiment, 147 wires are required for the service loop. Such a large service loop is problematic. Therefore, an alternative method has been developed in this preferred embodiment.
[0037]
FIG. 17 shows a relationship between each of the heating elements 78 attached to the slide rotor 77, and the heating element 78 is represented by a resistance element. A single sensor 87 is adjacent to each heater. The combination of a single heating element 78 and sensor 87 is located at a position 88 that heats a single slide. The physical layout of this location 88 is shown in FIGS. 14A and 14B. Two wires from each heating element and two wires from each sensor 87 are directly connected to a temperature control board mounted on the slide rotor 77. Each temperature control board can be connected to up to eight heater and sensor pairs. In this embodiment, seven boards 79 are attached to the lower side of the slide rotor to provide 49 slide positions, each of which is connected to seven pairs of heater sensors. One heater sensor position is not used for each temperature control board 79. Moreover, as shown in FIG. 17, the serial connection 89 of each of the seven temperature control boards is a daisy chain system with six wires. The first temperature control board is connected to the computer 86 via the service loop 90. The service loop is just six wires tied to the harness.
[0038]
FIG. 18 shows the arrangement of FIGS. 18A-D.
18A-D show the electronic circuit of the temperature control board 79. FIG. The design of the temperature control board 79 was urged to minimize the number of flexible cables (service loop 90) between the heater and the computer. In order to minimize the length of the wire, seven temperature control boards 79 are used, each of which is attached to the slide rotor. Thus, each heater is placed close to the corresponding electronic circuit, and each board 79 is reduced in size to control only the seven heating elements 78. Each temperature control board 79 has functions of an encoder and a decoder for temperature data. The above data relates to the measured value temperature and the target value temperature of each heating element 78. The data flow reciprocates between the computer 86 and the temperature control board 79. When it is necessary to raise or lower the temperature of a certain heating element 78, the computer transmits the information to the temperature control board 79. In response to this, the temperature control board 79 directly controls the amount of power sent to each heater. By arranging some of the logic circuits on the slide rotor in the form of a temperature control board 79, the number of wires in the service loop 90 and their length are minimized.
[0039]
In this embodiment, the temperature control board 79 system was designed as a shift register. The control microprocessor of the device sends one bit of data to the transmission line at a time and switches the clock line for each bit. As a result, data is sent through the two shift register chips U1 and U2 on each control board of 8 bits each. Therefore, 16 × 7, that is, 112 bits are sent out. According to FIGS. 18A-D, data enters connector J9.1 and the clock line is J9.2. The shift register used in this design is “double buffered”, which means that the output data does not change until a change occurs in the second clock (Rclock) entering pin J9.3. The two clocks are sent in parallel to all seven boards, while the data passes through the shift register chips (U1 and U2) on each board and follows the “serial output” pin SDOUT of the second shift register. Daisy-chained to the board's input pins. A matching connector J10 is connected in parallel with J9 except for pin 1. J10 is an “output” connector that connects a total of seven boards to J9 of the next board in the line via a short cable. The other three pins of J9 are used to power the electronic circuit (J9.4), electrical ground (J9.5) and common return line (J9.6) for temperature measurement function from the sensor.
[0040]
Eight of the 16 data bits in register U2 sent to each board directly control the on / off status of up to eight heating elements 78. This can be done with a single chip. This is because shift register U2 has internal power transistors that drive its output bits, each of which can directly control a high power load. Four of the remaining 8 bits are not used. The other 4 bits are used to select one thermistor 87 out of a total of 49 devices. To reduce economic reasons and wiring, the device has only one analog-to-digital converter and reads 49 temperature transducers (thermistors 87) and only one wiring sends data to this converter. This channel must therefore be shared among all transducers (thermistors 87) and selects one output at a time. The component U4 is an analog multiplexer that performs this function. One of the four digital bits received serially is used to add functionality to U4, and the other three are one of the component's eight channels (only seven of which are used). Used to select When pin 4 goes low, U4 for that board 79 becomes active and applies the voltage from one of the board's seven channels onto the shared output line of J9.6. Conversely, when pin 4 goes high, the output of U4 maintains a high impedance state and the output line is not driven. As a result, the data from the selected board 79 can be read, and the remaining boards 79 are not affected by the signal. The multiplexer U4 can only add functions to one board 79 at a time. If more than one are on at a time, the signals interfere with each other and no useful data is transmitted.
[0041]
Temperature sensing is realized by a voltage division method. A thermistor 87 and a fixed resistor (5.6 kilohms included in the RSI, R1-R8) are placed in series across the 5 volt power supply. When the thermistor is heated, the resistance decreases and the voltage at the junction with the 5.6 kohm resistor decreases.
[0042]
There are several advantages to the design used in this embodiment. That is, the temperature control board 79 is small in size and inexpensive. Furthermore, the heater boards are all the same. It is not necessary to set an “address” for each board 79. Accordingly, the size of the service loop 90 is small.
[0043]
An alternative design is to allow each temperature control board 79 to be set up with a permanent “address” formed by adding jumper wires or traces cut on the board. In this method, packet data including an address segment and a data segment is sent out, and the data is read into a board that matches the address from which the address was sent out. This method requires less time to send data to a particular board, but requires additional hardware for address comparison. This method also requires additional service loop wiring (if sent in parallel) to carry data, or additional shift register chips when sending addresses serially. Yet another possible design is that each temperature control board 79 has its own microprocessor. This method requires less connection wiring than the case of the present embodiment, but increases the hardware cost. This method further includes an addressing scheme, which means that the boards are not identical. In addition, a code for a microprocessor is required.
[0044]
[Equivalent]
While the invention has been described in detail with reference to preferred embodiments, workers skilled in the art will recognize that various changes can be made in form or detail without departing from the spirit and scope of the invention as defined by the claims. Let's go. Those skilled in the art will readily be able to envision many equivalents to the specific embodiments of the invention described herein without undue experimentation. Such equivalents are intended to be encompassed in the scope of the claims.
[Brief description of the drawings]
FIG. 1 is a perspective view of a slide staining apparatus according to a first embodiment of the present invention.
FIG. 2 is a plan view of a slide frame that forms five sealed voids on five different slides holding tissue samples.
FIG. 3 is a plan view of a slide frame base.
FIG. 4 is a bottom view of the slide frame housing.
FIG. 5 is a plan view of a slide frame housing with five microscope slides in their proper positions, showing the area to be heated.
FIG. 6 is a cross-sectional view of a slide frame placed on a slide rotor.
FIG. 7 is a schematic diagram of heater and sensor wiring on a slide frame and interconnection with a temperature controller.
FIG. 8 is a side sectional view of a cartridge pump distribution mechanism of a liquid distribution and removal station.
FIG. 9 is a cross-sectional side view of a large liquid dispensing station housed in a liquid dispensing and removal station.
FIG. 10A is a side cross-sectional view of a vacuum hose and a transport mechanism for removing a liquid reagent and a cleaning liquid from a slide included on a slide rotor.
FIG. 10B is a side sectional view of a vacuum hose and a transport mechanism for removing liquid reagent and cleaning liquid from a slide included on the slide rotor.
FIG. 11A is a side sectional view of the suction head and shows a relationship with a glass slide in a slide frame.
FIG. 11B is a plan view showing the bottom surface of the suction head.
FIG. 12 is a perspective view of a slide staining apparatus according to the second embodiment of the present invention.
FIG. 13 is a perspective view of a liquid handling zone of the same device.
FIG. 14A is a side sectional view of a liquid suction station according to a second embodiment, and a suction head is in a lowered position.
FIG. 14B is a side sectional view of the liquid suction station according to the second embodiment, and the suction head is in the raised position.
FIG. 15 is a schematic view showing a waste liquid path of a second embodiment.
FIG. 16 is a schematic view showing a large liquid distribution path of a second embodiment.
FIG. 17 is a schematic view of individual heaters on the slide rotor and a temperature control board mounted on the slide rotor.
FIG. 18 is a diagram showing an arrangement configuration of FIGS. 18A to 18D below.
FIG. 18A is a schematic diagram showing a part of an electronic circuit of a temperature control board.
FIG. 18B is a schematic diagram showing another part of the electronic circuit of the temperature control board.
FIG. 18C is a schematic diagram showing still another part of the electronic circuit of the temperature control board.
FIG. 18D is a schematic view showing still another part of the electronic circuit of the temperature control board.
[Explanation of symbols]
DESCRIPTION OF SYMBOLS 1 ... Slide dyeing apparatus, 3 ... Moving platform, 78 ... Heating element, 79 ... Temperature control electronic circuit, 87 ... Temperature sensor.

Claims (23)

A microscope slide staining apparatus having a random access slide staining function,
A moving platform of a carousel that supports a plurality of microscope slides carrying biological samples;
A plurality of heating element sets, each set having at least one heating element, heating at least one slide, each heating element set having a function of being heated to a different temperature. An element set;
Temperature control electronics attached to the mobile platform and supplying power to the heating element set;
A microscope slide staining apparatus comprising a user interface mounted remotely from the mobile platform and in communication with the temperature control electronics, through which a desired temperature for a microscope slide is specified.   2. The microscope slide staining apparatus according to claim 1, wherein the temperature control electronic circuit includes a shift register that receives control data from the user interface.   2. The microscope slide staining apparatus according to claim 1, further comprising a temperature sensor that provides temperature feedback information to the temperature control electronic circuit.   The microscope slide staining apparatus according to claim 1, wherein each heating element set heats a single slide.   The microscope slide staining apparatus according to claim 1, wherein each heating element set includes a flat slide support surface. A microscope slide staining apparatus having a random access slide staining function,
A plurality of microscope slides placed on a moving platform that is a carousel and carrying biological samples;
A plurality of heating element sets on the moving platform, each set having at least one heating element and capable of heating at least one slide, each set comprising another heating element Multiple heating element sets that can be heated to a different temperature than the set;
A user interface mounted at a location remote from the mobile platform to specify a desired temperature for each microscope slide, the user interface comprising electronic circuitry;
A microscope slide staining apparatus comprising: a wiring group that electrically connects the heating element on the moving platform and the user interface, wherein the number of wirings is smaller than the number of heater element sets. 7. The microscope slide staining apparatus according to claim 6 , further comprising temperature sensing means for providing temperature feedback data to the user interface. An automated device for the preparation or cultivation of biological samples,
A carousel moving platform supporting a plurality of biological samples;
A plurality of heaters disposed on the moving platform for supplying heat to one or more samples;
A computer mounted remotely from the mobile platform and specifying a desired temperature for each heater;
A controller for controlling the heating of each heater separately,
A plurality of temperature control electronics mounted on the mobile platform, each supplying power to at least one heater;
A data communication link between the computer and each of the temperature control electronics, wherein each of the temperature control electronics has an appropriate amount of power so that each heater is heated to a temperature specified by the computer. And a data communication link for supplying each of said heaters with a controller for controlling each heater separately. 9. The automated biological sample preparation or culture apparatus of claim 8 , wherein the biological sample is mounted on a microscope glass slide. 9. The automated biological sample preparation or culture apparatus of claim 8 , further comprising a temperature sensor that provides temperature feedback to the computer. A microscope slide staining apparatus having a random access slide staining function,
A moving platform of a carousel that supports a plurality of microscope slides carrying biological samples;
A plurality of heating means each for heating at least one slide, each heating means having a function of heating to a different temperature;
Temperature control means attached to the mobile platform for supplying power to the heating means;
A microscope slide staining apparatus comprising user interface means mounted remotely from the mobile platform and in communication with the temperature control means for specifying a desired temperature for each microscope slide.   2. The temperature control electronics of claim 1, wherein the temperature control electronics supplies power to each heating element set to heat at a multiple specified by the user interface, and each heating element set is at a different temperature than the other heating element sets. A microscope slide staining device that can be heated. A microscope slide staining apparatus having a random access slide staining function,
A moving platform of a carousel that supports a plurality of microscope slides carrying biological samples;
A plurality of heaters disposed on the moving platform, each heater heating at least one slide;
An independent temperature controller for controlling the heating of the heaters separately, comprising independent temperature controllers having temperature control electronics for supplying power to the heaters so that different samples can be heated to different temperatures; Microscope slide staining device. The microscope slide staining apparatus according to claim 13 , further comprising a plurality of temperature sensors, each sensor being incorporated in a heater. 14. The method of claim 13 , further comprising at least one reagent distributor capable of dispensing a liquid reagent to a microscope slide, wherein the moving platform moves a reagent from the reagent distributor on any slide under the reagent distributor. Microscope slide staining device that can be distributed. 14. The microscope slide stain according to claim 13 , further comprising a service loop connecting the temperature controller to a computer, wherein the temperature controller adjusts the amount of power to each heater so that each heater is heated to a desired temperature. apparatus. 14. The microscope slide staining apparatus according to claim 13, wherein the reagent is distributed at a fixed position from the reagent distributor. The microscope slide according to claim 13 , wherein the reagent distributor further comprises a liquid tank and a metering chamber, wherein the liquid flows out of the liquid tank and into the metering chamber before being dispensed onto the slide. Dyeing equipment. A staining protocol program with reagent application information and information on heating multiple microscope slides for mounting biological tissue;
A plurality of heating stations, each heating station comprising a heating element, wherein at least one microscope slide rests on the surface of each heating element so as to conduct heat to the at least one microscope slide;
At least one reagent distributor capable of dispensing a liquid reagent on a microscope slide;
A carousel moving platform capable of dispensing reagents from the reagent distributor onto a desired microscope slide under the reagent distributor as specified in the staining protocol program;
A computer that controls the functioning of the device to allow complete random access as specified in the staining protocol program, wherein the heating element heats the slide to different temperatures; Microscope slide staining device equipped with 20. The microscope slide staining apparatus according to claim 19 , wherein the moving platform moves the microscope slide and a reagent is dispensed in place from a reagent distributor. 20. The microscope slide staining apparatus according to claim 19, wherein each heating station heats only a single microscope slide. The microscope slide staining apparatus according to claim 19 , further comprising a plurality of sensors, each sensor being incorporated in a heating station. 20. The microscope slide according to claim 19 , wherein the reagent distributor further comprises a liquid tank and a metering chamber, and the liquid flows out of the liquid tank and into the metering chamber before being dispensed onto the slide. Dyeing equipment.

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